Cancer Stem Cells, Their Microenvironment and Anoikis.

Tumors are composed of a variety of cancer cells, all of which contribute to tumor heterogeneity. Among these populations of cells, cancer stem cells (CSCs) have an important role in the initiation and progression of cancer. CSCs are maintained extrinsically within the tumor microenvironment, which contains both cellular and physical factors. As a barrier to metastases, cells normally undergo apoptosis (cell death process) after they lose contact with their extracellular matrix or neighboring cells. This cell death process has been termed "anoikis". The tumor cells that acquire malignant potential develop mechanisms to resist anoikis. The tumor microenvironment has been acknowledged to contribute to anoikis resistance of bystander cancer cells via modulation of the matrix stiffness, enhancement of oxidative stress, production of pro-survival soluble factors, trigger of epithelial-mesenchymal transition (EMT), and self-renewal ability, thus leading to metabolic deregulations of cancer cells. In this article, we review the significance of perivascular cells, extracellular matrix, tumor stiffness, and hypoxia in the regulation of CSC plasticity and anoikis resistance. With a better understanding of the CSC interaction with its niche and anoikis resistance, it is possible to identify potential therapeutic targets for the development of more effective treatments against cancer.